The present invention relates to novel compounds and methods for the treatment of glaucoma and ocular hypertension. In particular, the present invention relates to the use of certain 11-aza analogs of F series prostaglandins to treat glaucoma and ocular hypertension.
Glaucoma is a progressive disease which leads to optic nerve damage and, ultimately, total loss of vision. The causes of this disease have been the subject of extensive studies for many years, but are still not fully understood. The principal symptom of and/or risk factor for the disease is elevated intraocular pressure or ocular hypertension due to excess aqueous humor in the anterior chamber of the eye.
The causes of aqueous humor accumulation in the anterior chamber are not fully understood. It is known that elevated intraocular pressure ("IOP") can be at least partially controlled by administering drugs which either reduce the production of aqueous humor within the eye, such as beta-blockers and carbonic anhydrase inhibitors, or increase the outflow of aqueous humor from the eye, such as miotics and sympathomimetics.
Most types of drugs conventionally used to treat glaucoma have potentially serious side effects. Miotics such as pilocarpine can cause blurring of vision and other visual side effects, which may lead either to decreased patient compliance or to termination of therapy. Systemically administered carbonic anhydrase inhibitors can also cause serious side effects such as nausea, dyspepsia, fatigue, and metabolic acidosis, which side effects can affect patient compliance and/or necessitate the termination of treatment. Another type of drug, beta-blockers, have increasingly become associated with serious pulmonary side effects attributable to their effects on beta-2 receptors in pulmonary tissue. Sympathomimetics, on the other hand, may cause tachycardia, arrhythmia and hypertension. Recently, certain prostaglandins and prostaglandin derivatives have been described in the art as being useful in reducing intraocular pressure. Typically, however, prostaglandin therapy for the treatment of elevated intraocular pressure is attended by undesirable side-effects, such as irritation and hyperemia of varying severity and duration. There is therefore a continuing need for therapies which control elevated intraocular pressure associated with glaucoma without the degree of undesirable side-effects attendant to most conventional therapies.
Prostaglandins are metabolite derivatives of arachidonic acid. Arachidonic acid in the body is converted to prostaglandin G.sub.2, which is subsequently converted to prostaglandin H.sub.2. Other naturally occurring prostaglandins are derivatives of prostaglandin H.sub.2. A number of different types of prostaglandins have been discovered including A, B, D, E, F, G, I and J-Series prostaglandins (EP 0 561 073 A1). Of interest in the present invention are compounds which are believed to exhibit IOP lowering mechanisms similar to those exhibited by PGF.sub.2.alpha. (an F-series prostaglandin): ##STR1##
The relationship of PGF.sub.2.alpha. receptor activation and IOP lowering effects is not well understood. It is believed that PGF.sub.2.alpha. receptor activation leads to increased outflow of aqueous humor. Regardless of the mechanism, PGF.sub.2.alpha. and certain of its analogs have been shown to lower IOP (Giuffre, The Effects of Prostaglandin F.sub.2.alpha. the Human Eye, Graefe's Archive Ophthalmology, volume 222, pages 139-141 (1985); and Kerstetter et al., Prostaglandin F.sub.2.alpha. -1-Isopropylester Lowers Intraocular Pressure Without Decreasing Aqueous Humor Flow, American Journal of Ophthalmology, volume 105, pages 30-34 (1988)). Thus, it has been of interest in the field to develop synthetic PGF.sub.2.alpha. analogs with IOP lowering efficacy.
Synthetic PGF.sub.2.alpha. -type analogs have been pursued in the art (Graefe's Archive Ophthalmology, volume 229, pages 411-413 (1991)). Though PGF.sub.2.alpha. -type molecules lower IOP, a number of these types of molecules have also been associated with undesirable side effects resulting from topical ophthalmic dosing. Such effects include an initial increase in IOP, breakdown of the blood aqueous barrier and conjunctival hyperemia (Alm, The Potential of Prostaglandin Derivatives in Glaucoma Therapy, Current Opinion in Ophthalmology, volume 4, No. 11, pages 44-50 (1993)). Based on the foregoing, a need exists for the development of molecules that may activate the PGF.sub.2.alpha. receptor yielding a more efficacious lowering of IOP, while exhibiting fewer or reduced side effects.
Stjernschantz et al. (U.S. Pat. No. 5,321,128), Woodward et al., (U.S. Pat. No. 5,093,329), Chan et al. (WO 92/08465) and Ueno et al. (EP 330 511 A.sub.2) have suggested synthetic prostaglandin analogs to reduce selectively or to eliminate altogether the side effects while maintaining the IOP-lowering effect. These synthetic prostaglandins, like their natural counterparts, all possess the core cyclopentane ring suggesting that it is important for IOP lowering activity.
An agent which exhibits comparable or improved efficacy, but with reduced side effects when compared to other agents, is said to have an improved therapeutic profile. It is an object of this invention to provide a class of IOP lowering agents with an improved therapeutic profile over PGF.sub.2.alpha. and methods of their use. It has now unexpectedly been discovered that the presently claimed 11-aza analogs of PGF.sub.2.alpha., in which the cyclopentane ring of endogenous prostaglandins is replaced by a pyrrolidine ring, meet this objective. Certain 11-aza analogs of prostaglandins have been reported in the literature (see, e.g., Rozing et al., Heterocycles, 7:123-9 (1977); Verdoorn et al., Synthetic Communications, 22:1813-29 (1992); and Holzapfel et al., South African Journal of Chemistry, 38:65-72 (1985), which are incorporated herein by reference). The compounds and methods of the present invention, however, are neither disclosed nor suggested in the foregoing art.